Neuropeptides, biogenic amines, and neurotrophins affect synaptic transmission by regulating pre- and postsynaptic function. The regulated release of these neuromodulators is mediated by the Ca2+-dependent fusion of dense-core vesicles (DCVs) with the plasma membrane. Although regulated DCV exocytosis is similar to the Ca2+-dependent exocytosis of synaptic vesicles (SVs) that mediate synaptic transmitter release, these processes differ in speed, latency, Ca2+ regulation and location. A fuller understanding of molecular mechanisms underlying Ca2+-triggered DCV fusion will reveal similarities and differences in the two vesicle fusion pathways that could identify unique drug targets for the selective inhibition of modulator secretion without inhibiting synaptic transmission. The protein CAPS (Ca2+-dependent activator protein in secretion) appears to be required for DCV but not SV exocytosis. We will elucidate the molecular mechanism of CAPS function in regulated DCV fusion and determine the physiological role of this protein in the nervous system. CAPS is a PIP2-binding protein that exhibits high affinity interactions with syntaxin, a key component of the SNARE fusion machinery. These interactions may mediate the function of CAPS at a late pre-fusion step in DCV exocytosis. CAPS also binds rabphilin, which may in part mediate CAPS interactions with DCVs. Our specific aims will be: 1. To determine the functional significance of CAPS-syntaxin interactions for DCV exocytosis;2. To determine if CAPS functions as a PIP2 effector in DCV exocytosis;3. To determine the basis for the selective role of CAPS in DCV exocytosis and whether this is mediated through rabphilin interactions;and 4. To determine the general role of CAPS in neural trafficking pathways that mediate neuropeptide, biogenic amine and neurotrophin secretion. The results from this work will contribute to understanding neural trafficking pathways and to the molecular basis for secretory vesicle fusion with the plasma membrane.